Cryptococcosis is a major cause of mortality in patients with AIDS, causing over 600,000 deaths per year worldwide. In recent years, cryptococcosis has also emerged as a major problem among organ transplant recipients. The treatment of cryptococcosis is unsatisfactory since the disease is associated with a high morbidity and mortality even following treatment with antifungal drugs. There is an acute need for new approaches to treatment in these populations at risk. Passive antibody therapy is a particularly promising approach. This competing application proposes a research plan to investigate a new problem in immunology, which has direct relevance to the development of antibody therapy for C. neoformans-related diseases, passive antibody therapies in general and our understanding of humoral immunity. In the past funding period, we have established that the constant region (C) domain of an immunoglobulin can affect the specificity of the antibody by a mechanism that is proposed to involve structural changes in the antigen-binding site. This finding challenges the long-held dogma in immunology that viewed immunoglobulin molecules as bifunctional molecules with two independent domains, composed of a C region and a variable (V) region. Our findings challenge this dogma, and in doing so suggest a need for revisions to our views on idiotype regulation, isotype restriction, generation of antibody responses, and generation of diversity in antibody repertories. At a practical level, these findings are critically important for the design and development of chimeric and humanized antibodies for human therapy and impact our analysis of vaccine responses. The research program proposes four aims: 1) To determine the structures and antigen contact residues for V-region identical Fab fragments derived from IgG1, IgG2a, IgG2b and IgG3;2) To identify the amino acid that mediate isotype-related differences in specificity among Abs with identical V regions;3) To establish whether constant region-mediated changes in specificity extend to IgM, IgE and IgA isotypes;and 4) Construction of a second-generation mouse-human chimeric Ab suitable for human trials. At the completion of these studies we will know how the C region affects V region conformation to influence affinity, specificity, and idiotype and we will have improved immunoglobulins to C. neoformans glucuronoxylomannan suitable for subsequent clinical studies.

Public Health Relevance

Antibodies are molecules that are critically important for defending against pathogenic microbes. This research proposal proposes to investigate how the structure of antibodies vary among different antibody types and how to then use this information to make better therapeutic reagents for treatment of a very serious fungal infection that affects individuals with compromised immune systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033774-19
Application #
8390490
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Lambros, Chris
Project Start
1993-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
19
Fiscal Year
2013
Total Cost
$386,199
Indirect Cost
$153,549
Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
De Leon-Rodriguez, Carlos M; Fu, Man Shun; Çorbali, M Osman et al. (2018) The Capsule of Cryptococcus neoformans Modulates Phagosomal pH through Its Acid-Base Properties. mSphere 3:
Vij, Raghav; Cordero, Radames J B; Casadevall, Arturo (2018) The Buoyancy of Cryptococcus neoformans Is Affected by Capsule Size. mSphere 3:
Casadevall, Arturo (2018) Antibody-based vaccine strategies against intracellular pathogens. Curr Opin Immunol 53:74-80
Jung, Eric H; Meyers, David J; Bosch, Jürgen et al. (2018) Novel Antifungal Compounds Discovered in Medicines for Malaria Venture's Malaria Box. mSphere 3:
Goldman, David L; Nieves, Edward; Nakouzi, Antonio et al. (2018) Serum-Mediated Cleavage of Bacillus anthracis Protective Antigen Is a Two-Step Process That Involves a Serum Carboxypeptidase. mSphere 3:
Fu, Man Shun; Casadevall, Arturo (2018) Divalent Metal Cations Potentiate the Predatory Capacity of Amoeba for Cryptococcus neoformans. Appl Environ Microbiol 84:
Casadevall, Arturo (2018) Fungal Diseases in the 21st Century: The Near and Far Horizons. Pathog Immun 3:183-196
De Leon-Rodriguez, Carlos M; Rossi, Diego C P; Fu, Man Shun et al. (2018) The Outcome of the Cryptococcus neoformans-Macrophage Interaction Depends on Phagolysosomal Membrane Integrity. J Immunol 201:583-603
Walker, Louise; Sood, Prashant; Lenardon, Megan D et al. (2018) The Viscoelastic Properties of the Fungal Cell Wall Allow Traffic of AmBisome as Intact Liposome Vesicles. MBio 9:
Pirofski, Liise-Anne; Casadevall, Arturo (2017) Immune-Mediated Damage Completes the Parabola: Cryptococcus neoformans Pathogenesis Can Reflect the Outcome of a Weak or Strong Immune Response. MBio 8:

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